Project Summary Oropharyngeal candidiasis (OPC) is still a common disease of HIV-infected people, despite the availability of antiretroviral therapy. The long-term goal of this work is to develop new treatments for oral fungal disease in HIV patients. Treatments must be effective against Candida albicans, the most common cause of OPC, and also other pathogenic Candida species. Because adhesion of fungal cells to the oral mucosa is required for OPC, interfering with fungal adhesion would eliminate colonization and subsequent disease. The agglutinin-like sequence (Als) proteins of C. albicans play a key role in adhesion of fungal cells to oral surfaces. Recent crystallographic solution of the structure of the Als adhesive domain revealed a peptide-binding cavity that is responsible for the adhesive interaction between C. albicans and oral epithelial cells. Because Als proteins are found in other pathogenic Candida species that cause OPC, they are prime targets for development of anti-adhesive therapies. However, ALS sequences in published genomes for these species are incorrectly assembled so the composition of and variability in the fungal ALS family remain unknown. This situation echoes similar problems that occurred during assembly of the C. albicans genome sequence and can be remedied through laboratory experimentation to define each ALS gene and its unique physical locus. This project will derive accurate DNA sequences for the ALS genes in the pathogenic Candida species that cause OPC. Gene expression analysis will indicate which encoded proteins are likely to have a major presence on the fungal cell surface. Candidate proteins will be selected for subsequent structural analyses and design of adhesive inhibitors that will be effective against multiple fungal species. This AREA proposal will involve undergraduate students from the University of Illinois and Millikin University. Students will learn computer-based analysis of genome data and gain valuable molecular biology laboratory skills. The project will enhance the research environment of both institutions and overcome a critical barrier to progress in the development of Als-based anti-adhesive therapies.